Isoxazole-isoxazoles and isoxazole-isothiazoles
The present invention is concerned with isoxazole-isoxazoles and isoxazole-isothiazoles of formula I, having affinity and selectivity for GABA A α5 receptor, their manufacture, pharmaceutical compositions containing them and their use as cognitive enhancers or for the therapeutic and/or prophylactic treatment of cognitive disorders like Alzheimer's disease.
1. A compound of formula I,
wherein
R 1 is lower alkyl, optionally substituted by halogen, cyano, hydroxy, lower-alkoxy or halogen-lower-alkoxy,
aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which is optionally substituted by halogen, cyano, hydroxy, lower alkyl, halogen-lower alkyl, cyano-lower alkyl, hydroxy-lower alkyl, lower alkyl-C(═O)OH, lower alkyl-C(═O)O-lower alkyl, lower alkyl-CO—NR 5 R 6 , lower alkyl-NR 5 R 6 , lower-alkoxy-lower alkyl, —CO-lower alkyl, —C(═O)OH, —C(═O)O-lower alkyl, —CONR 5 R 6 , —NR 5 R 6 , lower-alkoxy, halogen-lower-alkoxy, —SO 2 -lower alkyl, —SO 2 —NR 5 R 6 , cycloalkyl, phenyloxy or phenyl,
R 2 is lower alkyl optionally substituted by halogen, cyano, hydroxy, lower-alkoxy or halogen-lower-alkoxy,
R 3 is lower alkyl, optionally substituted by carboxy, halogen or hydroxyl;
aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which is optionally substituted by carboxy, halogen, hydroxy or lower alkyl; or
—NR 7 R 8 ,
R 4 is H or lower alkyl,
or R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring,
R 5 is H or lower alkyl,
R 6 is H or lower alkyl,
R 7 is H or lower alkyl,
R 8 is H or lower alkyl,
Y is O or S, and
X is CH 2 —O— or —CH═CH—,
or a pharmaceutically active salt or ester thereof.
2. The compound of claim 1 , wherein Y is O.
3. The compound of claim 1 , wherein Y is S.
4. The compound of claim 1 , wherein X is —CH 2 —O—.
5. The compound of claim 1 , wherein X is —CH═CH—.
6. The compound of claim 1 , wherein R 2 is lower alkyl or hydroxy-lower alkyl.
7. The compound of claim 1 , wherein R 2 is Me or hydroxy-Me.
8. The compound of claim 1 , wherein R 1 is aryl, aryl substituted by halogen, heteroaryl, or heteroaryl substituted by halogen.
9. The compound of claim 1 , wherein R 1 is Ph, 4-fluoro-Ph, pyridinyl or 3-fluoro-pyridinyl.
10. The compound of claim 1 , wherein R 4 is H.
11. The compound of claim 1 , wherein R 3 is lower alkyl, lower alkyl substituted by hydroxyl, lower alkyl substituted by carboxy, lower alkyl substituted by halogen, heterocyclyl, or —NR 7 R 8 , wherein R 7 and R 8 are each independently lower alkyl.
12. The compound of claim 1 , wherein R 3 is 2,2,2-trifluoro-ethyl-, 2-carboxyethyl-, 2-hydroxy-1-methyl-ethyl-, 2-hydroxy-ethyl-, 3-tetrahydrofuranyl-, 4-tetrahydropuranyl-, isopropyl-, (CH 3 ) 2 N—, piperidinyl, pyrrolidinyl or morpholino.
13. The compound of claim 1 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form 2-oxa-6-aza-spiro[3.3]hept-6-yl.
14. The compound of claim 1 , selected from the group consisting of
3-[(E)-2-(3-Butyl-5-methyl-isoxazol-4-yl)-vinyl]-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid isopropylamide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide,
Acetic acid 2-{[3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carbonyl]-amino}-ethyl ester,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid N′,N′-dimethyl-hydrazide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-ylamide, and
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid pyrrolidin-1-ylamide
or a pharmaceutically active salt or ester thereof.
15. The compound of claim 1 , selected from the group consisting of
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid isopropyl amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2,2,2-trifluoro-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid N′,N′-dimethyl-hydrazide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-ylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid pyrrolidin-1-ylamide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid isopropylamide, and
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide
or a pharmaceutically active salt or ester thereof.
16. The compound of claim 1 , selected from the group consisting of
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid isopropylamide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3(S)-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3(R)-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid N′,N′-dimethyl-hydrazide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide, and
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid isopropylamide
or a pharmaceutically active salt or ester thereof.
17. The compound of claim 1 , selected from the group consisting of
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid isopropyl amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid isopropylamide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
{3-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazol-5-yl}-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone
3-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid isopropylamide
3-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide, and
3-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (2,2,2-trifluoro-ethyl)-amide
or a pharmaceutically active salt or ester thereof.
18. A compound of claim 1 , selected from the group consisting of
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid isopropylamide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide,
Acetic acid 2-{[3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carbonyl]-amino}-ethyl ester,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-ylamide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid pyrrolidin-1-ylamide, and
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide
or a pharmaceutically active salt or ester thereof.
19. A compound of claim 1 , selected from the group consisting of
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid isopropyl amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2,2,2-trifluoro-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid N′,N′-dimethyl-hydrazide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-ylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid pyrrolidin-1-ylamide, and
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid isopropylamide
or a pharmaceutically active salt or ester thereof.
20. A compound of claim 1 , selected from the group consisting of
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3(R)-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3(S)-yl)-amide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid isopropyl amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid isopropylamide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide, and
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
or a pharmaceutically active salt or ester thereof.
21. A compound of claim 1 , selected from the group consisting of
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid isopropylamide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2,2,2-trifluoro-ethyl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid isopropyl amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid morpholin-4-ylamide,
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3(S)-yl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (2-hydroxy-ethyl)-amide,
3-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide,
3-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-ylamide, and
3-(3-Butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3(R)-yl)-amide,
or a pharmaceutically active salt or ester thereof.
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
R 1 is lower alkyl, optionally substituted by halogen, cyano, hydroxy, lower-alkoxy or halogen-lower-alkoxy,
aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which is optionally substituted by halogen, cyano, hydroxy, lower alkyl, halogen-lower alkyl, cyano-lower alkyl, hydroxy-lower alkyl, lower alkyl-C(═O)OH, lower alkyl-C(═O)O-lower alkyl, lower alkyl-CO—NR 5 R 6 , lower alkyl-NR 5 R 6 , lower-alkoxy-lower alkyl, —CO-lower alkyl, —C(═O)OH, —C(═O)O-lower alkyl, —CONR 5 R 6 , —NR 5 R 6 , lower-alkoxy, halogen-lower-alkoxy, —SO 2 -lower alkyl, —SO 2 —NR 5 R 6 , cycloalkyl, phenyloxy or phenyl,
R 2 is lower alkyl optionally substituted by halogen, cyano, hydroxy, lower-alkoxy or halogen-lower-alkoxy,
R 3 is lower alkyl, optionally substituted by carboxy, halogen or hydroxyl;
aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which is optionally substituted by carboxy, halogen, hydroxy or lower alkyl; or
—NR 7 R 8 ,
R 4 is H or lower alkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring,
R 5 is H or lower alkyl,
R 6 is H or lower alkyl,
R 7 is H or lower alkyl,
R 8 is H or lower alkyl,
Y is O or S, and
X is CH 2 —O— or —CH═CH—,
or pharmaceutically active salt or ester thereof and a pharmaceutically acceptable carrier.